For several years work in this laboratory has focused on the role of rheumatoid factor in human disease. We were particularly interested in evaluating the interaction between rheumatoid factors and complement and how immune complexes or aggregates might consequently be affected. During the past years our attention has been directed more towards the actual pathogenetic effects of immune complexes, particularly as they affect lymphocyte function and various target organs. Recent evidence suggests that lymphocytes in patients with systemic lupus erythematosus may be regulated by aggregated IgG or immune complexes, as well as by antilymphocyte antibodies. It will be an important aim of our studies to characterize the relationship between circulating humoral factors and depressed cellular functions. The specific objective of this proposal is an evaluation of certain serum factors which directly or indirectly mediate injury in systemic lupus erythematosus and rheumatoid arthritis. These factors would appear to fall into three main groups: 1) antigen-antibody complexes or aggregates which may cause injury directly to susceptible organs and tissues; 2) regulator globulins and antibodies which may inhibit host cellular function by interaction with the lymphocyte membrane; and 3) substances such as rheumatoid factors and complement which may modify the factors noted in (1) and (2) above. We hope that by more precisely defining the roles of these various factors in these rheumatic diseases a clearer understanding of pathogenetic mechanisms and modes of therapy should emerge. Conceivably in the course of evaluating these various factors an important new antigen (or antigens) may be uncovered; this might be a clue leading to an inciting factor (or factors) in one or more of the connective tissue diseases.